Peptide and protein conformations comprise one of the principal determinates of biofunction and bioavailabilty. The ability to induce or restrict peptide/protein conformation and thereby reduce polarity, increase proteolytic stability, and/or improve drugability, peptide/protein macrocyclization has become an effective, well recognized tactic. ((a) Marsault, E.; Peterson, M. L. Journal of Medicinal Chemistry 2011, 54, 1961-2004. (b) White, C. J.; Yudin, A. K. Nature Chemistry 2011, 3, 509-524.)
The development of an all hydrocarbon-stapling tactic has provided a number of bioactive peptides, locked into their active conformation, to target intracellular protein-protein interactions. Alternative examples of helix stabilization include side chain tethering of peptides/proteins with amides, triazoles or oximes linkages. Spokoyny and co-workers recently employed perfluoroarylation to stabilize α-helical conformations between two cysteine residues, resulting in enhanced cell permeability and increased chemical stability. (Spokoyny, A. M., et al. J. Am. Chem. Soc. 2013. 135, 5946-5949.). Methods to readily insert a staple and to remove an inserted staple—without severely disrupting the peptide/protein—are needed.